Glioblastoma multiforme is the most common primary malignant brain cancer and has an extremely aggressive growth pattern and a dismal prognosis. Surgical and chemoradiation have made some progress, but the life expectancy remains around 15–18 months after diagnosis. Targeted toxins are a class of medications that have seen significant success in the hematologic malignancies such as leukemia and lymphoma. Targeted toxins utilize antigen or receptor overexpression to home anticancer agents to concentrate inside tumor cells and offer the possibility of highly efficacious systemically administered medications while also decreasing systemic side effects. This chapter will detail the progress made toward developing and refining a targeted toxin approach to treatment of high-grade gliomas.